Action of substance P (neurokinin-1) receptor activation on rat neostriatal projection neurons

Abstract

Substance P (SP) acts as a neurotransmitter in the neostriatum through the axon collaterals of spiny projection neurons. However, possible direct or indirect actions of SP on the neostriatal output neurons have not been described. Targets of SP terminals within the neostriatum include interneurons, spiny neurons, afferent fibers and boutons. SP induces the release of both dopamine (DA) and acetylcholine (ACh). Since some postsynaptic actions of both DA and ACh on spiny neurons are known, we asked if activation of neostriatal NK1-class receptors is able to reproduce them. The SP NK1-receptor agonist, GR73632 (1 microM), had both excitatory and inhibitory actions on virtually all spiny neurons tested at resting potential. The excitatory action was blocked by atropine and coursed with an increase in firing rate and input resistance (R(N)). The inhibitory action was blocked by haloperidol and coursed with a reduction in firing rate and R(N). Therefore, the release of both DA and ACh induced by NK1-receptor activation modulates indirectly the excitability of the projection neurons. SP facilitates the actions of these transmitters on the spiny neuron. A residual excitatory response to the NK1-receptor agonist was observed in 30% of a sample of neurons tested in the presence of both haloperidol and atropine. The increase in R(N) that accompanied this response could be observed in the presence of 1 microM TTX or 100 microM Cd2+, suggesting a direct effect. Double labeling showed that only SP-immunoreactive neurons were facilitated by NK1-receptor activation in these conditions.

Neurokinin 1 receptor distribution in cholinergic neurons and targets of substance P terminals in the rat nucleus accumbens

“…Furthermore, in this region, SP‐immunoreactive terminals form synapses with cholinergic dendrites (Martone et al, 1992), suggesting that the functional sites for NK1 receptor activation are at these synapses. Synaptic transmission is consistent with the known calcium dependence of NK1 receptor‐mediated excitation of cholinergic striatal neurons (Bell et al, 1998) that is believed to be largely responsible for the atropine‐sensitive, SP‐evoked excitation of spiny projection neurons (Galarraga et al, 1999). A recent ultrastructural study has suggested, however, that, in the CPN, SP is released from sites that are remote from NK1 receptors, supporting a paracrine mode of transmission (Li et al, 2000).…”

Neurokinin-1 receptor activation in globus pallidus

“…As most striatal neurons are quiescent (Chevalier and Deniau, 1990), the facilitation on sIPSCs observed in the present studies is consistent with the scenario that excitation of pallidal neurons resulted in action potential dependent GABA release from their collaterals. However, since substance P also exerted both excitatory and inhibitory actions on striatal projection neurons (Galarraga et al, 1999), we cannot rule out the possibility of increased GABA release from striatum. Morphological and electrophysiological studies have revealed that subthalamic nucleus is the major glutamatergic input onto the globus pallidus.…”

Synergism between methamphetamine and the neuropeptide substance P on the production of nitric oxide in the striatum of mice

“…Intrathecal injection of GR-73632 in the spinal cord of mice caused dose-dependent behavioral responses such as scratching, biting and licking that were inhibited by the co-administration of a neurokinin-1 receptor antagonist (Sakurada et al, 1999). Moreover, in similar fashion to substance P, the infusion of GR-73632 elicited dopamine and acetylcholine turnover in the striatum (Galarraga et al, 1999). Our data show that the intrastriatal injection of GR-73632 induced the production of NO and this induction was attenuated by the co-administration of WIN-51,708.…”